What question did this study set out to answer?

Investigate the potential of PD-L1/HVEM-engineered islet cells to induce transplant tolerance and enhance graft survival in diabetes.

June 10, 2026

1315-OR: Escaping Rejection: PD–L1/HVEM–Engineered β-Cells for Durable Transplant Survival

Key Points

Investigate the potential of PD-L1/HVEM-engineered islet cells to induce transplant tolerance and enhance graft survival in diabetes.
Used NOD mice to test PD-L1 and HVEM as optimal ligands in allo-transplantation models.
Engineered β cells with ligands via click chemistry and monitored glucose control and graft survival post-transplant.
Conducted Treg depletion and lymphocyte transfer experiments to explore immune mechanisms involved.
PD-L1/HVEM-engineered grafts resulted in durable glucose control across all transplant models without immunosuppression.
Treg depletion led to loss of grafts, indicating their crucial role in maintaining tolerance.
Lymphocytes from tolerant donor mice were able to induce tolerance in new recipients with non-engineered grafts.

Abstract

Introduction and Objective: Islet allo-transplantation can potentially cure type 1 diabetes (T1D), but immune rejection and systemic immunosuppression remain key challenges. Inspired by cancer immunotherapy, we hypothesized that engineering islet cells with checkpoint ligands could induce transplant tolerance. Our lab previously showed that autologous β cells reverse autoimmunity in NOD mice. Here, we demonstrate proof of concept for applying checkpoint engineering to allo-transplantation. Methods: Using NOD mice, we identified PD-L1 and HVEM as the optimal ligand combination. This was applied to three allo-transplantation models: B6-ES-β into STZ-diabetic BALB/c, B6-ES-β into newly diabetic NOD, and BALB/c islets into STZ-diabetic B6. β cells or islets were engineered via click chemistry and mixed with pancreatic ECM before subcutaneous transplantation. Blood glucose and graft survival were monitored. Treg depletion and adoptive transfer explored mechanisms. Results: In all models, PD-L1/HVEM-engineered grafts achieved durable glucose control without immunosuppression. Treg depletion caused graft loss. Adoptive transfer of lymphocytes from tolerant mice induced tolerance in new recipients even with non-engineered grafts, indicating transferable regulatory immunity. Conclusion: Checkpoint-engineered islets induced tolerance by promoting regulatory T cells and improving graft survival, offering strong translational potential. Disclosure L. Ruan: None. M. Wang: None. J.T. Peters: None. A.Z. Wang: None.

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